1. Technical Field
The invention relates to methods for reducing an imine to an amine, and more specifically to the enantioselective reduction of an imine using a chiral reducing agent to generate a chiral amine product of enhanced enantiomeric excess.
2. Background Art
As disclosed in Fox et al., "A First Generation Calcimimetic Compound (NPS R-568) that Acts on the Parathyroid Cell Calcium Receptor: A Novel Therapeutic Approach for Hyperparathyroidism," Journal of Bone and Mineral Research, 8: S181, Abstract 260 (Suppl. 1, Aug., 1993), compounds such as (R)-(+)-N-[1-(3-methoxyphenyl)ethyl]-3-(2-chlorophenyl)propanamine (chem. abstr. index name, also known as, e.g., (R)-(+)-N-[3-(2-chlorophenyl)propyl-.alpha.-methyl-3-methoxybenzylamine or (R)-(+)-N-[3-(2-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine), i.e.: ##STR2## have utility in the treatment of hyperparathyroidism and possibly other bone and mineral-related disorders and diseases such as osteoporosis.
As disclosed in Zhu et al. "Asymmetric Reductions of Carbon-Nitrogen Double Bonds. A Review", Organic Preparation and Procedures International., 26 (2)193-236 (1994): "Reagents prepared from reaction of LiAlH.sub.4 with (-)-menthol or (+)-borneol were used to reduce several aliphatic imines to the corresponding mines, but the enantiomeric excesses obtained were low (i.e., 1.8-9.9% ee). Also, the use of optically active .alpha.-phenylethylamine-borane complex for the reductive amination of prochiral ketones to produce chiral amines has also been investigated, but gave very low enantioselectivities (1.1-1.6% ee)."
Although the successful chiral reduction of ketones to alcohols has been thoroughly documented in the literature, the reductions of imines to chiral amines, as indicated above (from Zhu et at.), has given, at best, poor yields (&lt;10% ee). A straightforward chemical synthesis yielding (R)-(+)-N-[3-(2-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, and similar analogs (in greater than 10% ee), using readily available inexpensive, and achiral starting materials would be an improvement in the art.